Dual‐Gene Edited Extracellular Vesicles Remodel the Redox Homeostasis to Inhibit Ferroptosis in Intervertebral Disc Degeneration
Jing Yan, Yazhou Lin, Shuo Miao, Minghao Chao, Chengbai Dai, Ziwen Hao, Rui Chen, Ming Guan, Bin Pan, Fenglei Gao, Quan ZhouABSTRACT
Intervertebral disc degeneration (IDD) is driven by ferroptosis of nucleus pulposus cells (NPCs) as a core pathological mechanism. Nucleus pulposus progenitor cells (NPPCs), exhibiting stem cell‐like properties, yield extracellular vesicles (PEVs) with high affinity for NPCs and enable targeted phenotypic regulation. However, natural PEVs possess limited bioactivity. Therefore, we constructed engineered mFD‐PEVs modified with FTH1 and DAB2. In vitro experiments demonstrated that mFD‐PEVs efficiently deliver FTH1, maintained SLC7A11/GPX4‐associated redox defense, suppress NPCs oxidative stress, and attenuate ferroptosis. Furthermore, in vivo studies confirmed the potent therapeutic efficacy of mFD‐PEVs in promoting intervertebral disc regeneration. Transcriptomic analysis further revealed that mFD‐PEVs predominantly modulate molecular pathways associated with ferroptosis and oxidative stress. In summary, the gene‐edited mFD‐PEVs reprogram redox homeostasis in NPCs, regulate ferroptosis, and promote intervertebral disc regeneration.